Field of the Invention
Compounds of this invention are analogues of natural prostaglandins.
Natural prostaglandins are twenty-carbon atom alicyclic compounds related to prostanoic acid which has the following structure: ##STR1## By convention, the carbon atoms of I are numbered sequentially from the carboxylic carbon atom. An important stereochemical feature of I is the trans-orientation of the side chains C.sub.1 -C.sub.7 and C.sub.13 -C.sub.20. In I, as elsewhere in this specification, a dashed line (---) indicates projection of a covalent bond below the plane of a reference carbon atom (alpha-configuration), while a wedged line ( ) represents direction above that plane (beta-configuration). Those conventions apply to all compounds subsequently discussed in this specification.
Natural prostaglandins have the structure, ##STR2## in which: L and M may be ethylene or vinylene radicals and the five-membered ring ##STR3## may be: ##STR4##
Prostaglandins are classified according to the functional groups present in the five-membered ring and the presence of double bonds in the ring or chains. Prostaglandins of the A-class (PGA) are characterized by an oxo group at C.sub.9 and a double bond at C.sub.10 -C.sub.11 (.DELTA..sup.10,11); those of the B-class (PGB) have an oxo group at C.sub.9 and a double bond at C.sub.8 -C.sub.12 (.DELTA..sup.8,12); compounds of the C-class (PGC) contain an oxo group at C.sub.9 and a double bond at C.sub.11 -C.sub.12 (.DELTA..sup.11,12); members of the D-class (PGD) have an oxo group at C.sub.11 and an alpha-oriented hydroxy group at C.sub.9 ; prostaglandins of the E-class (PGE) have an oxo group at C.sub.9 and an alpha-oriented hydroxyl grop at C.sub.11 ; and members of the F-class (PGF) have either an alpha- or beta-directed hydroxyl group at C.sub.9 and an alpha-oriented group at C.sub.11. Within each of the A, B, C, D, E, and F classes of prostaglandins are three subclassifications based upon the presence of double bonds in the side chains at C.sub.5 -C.sub.6, C.sub.13 -C.sub.14, or C.sub.17 -C.sub.18. The presence of a trans-unsaturated bond only at C.sub.13 -C.sub.14 is indicated by the subscript numeral 1; thus, for example, PGE.sub.1 denotes a prostaglandin of the E-type (oxo group at C.sub.9 and an alpha-hydroxyl at C.sub.11) with a trans-double bond at C.sub.13 -C.sub.14. The presence of both a trans-double bond at C.sub.13 -C.sub.14 and a cis-unsaturated bond at C.sub.5 -C.sub.6 is denoted by the subscript numeral 2; for example, PGE.sub.2. Lastly, a trans-double bond at C.sub.13 -C.sub.14, a cis-double bond at C.sub.5 -C.sub.6 and a cis-double bond at C.sub.17 -C.sub.18 is indicated by the subscript numeral 3; for example, PGE.sub.3. The above notations apply to prostaglandins of the A, B, C, D, and F series as well, however, in the latter the alpha-orientation of the hydroxyl group at C.sub.9 is indicated by the subscript Greek letter .alpha. after the numerical subscript. A similar convention applies to PGF molecules in which the C.sub.9 hydroxyl has the .beta.-orientation. Thus, PGF.sub.3.alpha. represents 9.alpha.,11.alpha.,15.alpha.-trihydroxy-5,17-cis, 13-trans-prostatrienoic acid (utilizing nomenclature based upon prostanoic acid).
It is important to note that in all natural prostaglandins there is an alpha-oriented hydroxyl group at C.sub.15. In the Cahn-Ingold-Prelog system of defining stereochemistry, that C.sub.15 hydroxyl group is in the S-configuration.
11-Deoxy derivatives of PGE and PGF molecules do not occur as such in nature, but constitute a class of compounds which possess biological activity related to the parent compounds. Formula II represents 11-deoxy PGE and PGF compounds when ##STR5##
I.U.P.A.C. nomenclature of prostaglandins designates the carboxylic side chain as the parent compound: for example, PGF.sub.3.alpha. is 7-{3.alpha., 5.alpha.-dihydroxy-2.beta.-[(3S)-3-hydroxy-trans-1, cis-5-oxtenyl]-1.alpha.-cyclopentyl}-cis-5-heptenoic acid.
Recent research indicates that prostaglandins are ubiquitous in animal tissues and that prostaglandins, as well as their synthetic analogues, have important biochemical and physiological effects in mammalian endocrine, reproductive, central and peripheral nervous, sensory, gastro-intestinal, hematic, respiratory, cardiovascular, and renal systems.
In mammalian endocrine systems, experimental evidence indicates prostaglandins are involved in the control of hormone synthesis or release in hormone-secretory glands. In rats, for example, PGE.sub.1 and PGE.sub.2 increase release of growth hormone while PGA.sub.1 increased synthesis of that hormone. In sheep, PGE.sub.1 and PGF.sub.1.alpha. inhibit ovarian progesterone secretion. In a variety of mammals, PGF.sub.1.alpha. and PGF.sub.2.alpha. act as luteolytic factors. In mice, PGE.sub.1, PGE.sub.2, PGF.sub.1.alpha. and PGE.sub.1.beta. increase thyroid activity. In hypophysectomized rats, PGE.sub.1, PGE.sub.2 and PGF.sub.1.alpha. stimulate steroidogenesis in the adrenal glands.
In the mammalian male reproductive systen, PGE.sub.1 contracts the smooth muscle of the vas deferens. In the female reproductive system, PGE and PGF.sub..alpha. compounds contract uterine smooth muscle. In general, PGE, PGB and PGA compounds relax in vitro human uterine muscle strips, while those of the PGF.sub..alpha. class contract such isolated preparations. PGE compounds in general promote fertility in the female reproductive system while PGF.sub.2.alpha. has contragestational effects. PGF.sub.2.alpha. also appears to be involved in the mechanism of menstruation. In general, PGE.sub.2 exerts potent oxytocic effects in inducing labor, while PGF.sub.2.alpha. induces spontaneous abortions in early pregnancy.
PGF.sub..alpha. and PGE compounds have been isolated from a variety of nervous tissue and they seem to act as neurotransmitters. PGE.sub.1 retards whereas PGF.sub.2.alpha. facilitates transmission in motor pathways in the central nervous system. It has been reported that PGE.sub.1 and PGE.sub.2 inhibit transmitter release from adrenergic nerve endings in the guinea pig.
Prostaglandins stimulate contraction of gastrointestinal smooth muscle in vivo and in vitro. In dogs, PGA.sub.1, PGE.sub.1 and PGE.sub.2 inhibit gastric secretion. PGA.sub.1 exhibits similar activity in man.
In most mammalian respiratory tracts, compounds of the PGE and PGF class relax in vitro preparations of tracheal smooth muscle. In that preparation, PGE.sub.1 and PGE.sub.2 relax while PGF.sub.2.alpha. contracts the smooth muscle. PGE and PGF compounds are normally found in the human lung, and it is postulated that some cases of bronchial asthma involve an imbalance in the production or metabolism of those compounds.
Prostaglandins are involved in certain hematic mechanisms in mammals. PGE.sub.1, for example, inhibits thrombogenesis in vitro through its effects on blood platelets.
In a variety of mammalian cardiovascular systems, compounds of the PGE and PGA class are vasodilators whereas those of the PGF.sub..alpha. class are vasoconstrictors, by vitrue of their action on vascular smooth muscle.
Prostaglandins are naturally found in the kidney and reverse experimental and clinical renoprival hypertension.
The clinical implications of prostaglandins and their analogues are far-ranging and include, but are not limited to the following: in obstetrics and gynecology, they may be useful in fertility control, treatment of menstrual disorders, induction of labor, and correction of hormone disorders; in gastroenterology, they may be useful in the treatment of peptic ulcers and various disorders involving motility, secretion, and absorption in the gastrointestinal tract; in the respiratory area, they may be beneficial in the therapy of bronchial asthma and other diseases involving bronchoconstriction; in hematology, they may have utility as anti-clotting agents in diseases such as venous thrombosis, thrombotic coronary occlusion and other diseases involving thrombi; in circulatory diseases they may have therapeutic utility in hypertension, peripheral vasopathies, and cardiac disorders.
For a more complete review of chemical, physiological and pharmacological aspects of the prostaglandin, consult the following references: The Prostaglandins, Vol. I., P. Ramwell, Ed., New York, Plenum Press, 1973; Ann, N.Y. Acad. Sci., 180: 1-568 (1971); and Higgins and Braunwald, J. Am. Med. Assn., 53: 92-112 (1972.).